scholarly journals Novel Splice-Site and Missense Variant of PNPLA6 in an Austrian Family Causing Spastic Paraplegia-39 with Cerebellar Oculomotor Disorder

2022 ◽  
Author(s):  
Sebastian Viertauer ◽  
Ingo Kurth ◽  
Katja Eggermann ◽  
Christian Eggers
Keyword(s):  
Splice Site ◽  
Lower Limb ◽  
Clinical Symptoms ◽  
Hypogonadotropic Hypogonadism ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Spastic Paraplegia ◽  
Meaningful Improvement ◽  
Pathogenic Variants ◽  
Splice Site Variant

Abstract Background The term hereditary spastic paraplegia comprises an ever-expanding array of neurological disorders with distinct aetiologies. Spastic paraplegia 39 is one of the many variants with additional features of other organs and neurological systems. We describe a large kindred with two hitherto undescribed mutations of PNPLA6 and a novel clinical phenotype as, in addition to spastic paraplegia, affected subjects suffered from a prominent cerebellar oculomotor dysfunction. Methods Three of five genetically tested family members of a large kindred were affected by spastic gait and cerebellar oculomotor dysfunction. Clinical, imaging, laboratory and electrophysiological data were analyzed. Genetic analysis was done using next-generation sequencing. Segregation analyses were performed by Sanger sequencing. To assess the pathogenicity of genetic variants on the encoded protein, in silico assessments were carried out. Results Two hitherto unknown sequence variants in the PNPLA6 gene, a splice-site variant c.1635+3G>T and a missense variant c.3401A>T, p.(Asp1134Val), were detected. Compound-heterozygous siblings presented with lower limb spasticity and a marked cerebellar oculomotor disorder accompanied by moderate hypogonadotropic hypogonadism in the female. A paternal uncle being homozygous for the splice-site variant of PNPLA6 presented with increased lower limb reflexes, an unstable gait and cerebellar oculomotor dysfunction. Treatment with 4-aminopyridin, a potassium channel blocker, lead to meaningful improvement of clinical symptoms. Conclusion PNPLA6 gene variants are associated with a broad phenotypic spectrum to which we add cerebellar oculomotor dysfunction. In our kindred, the full clinical manifestation only occurred in compound-heterozygous subjects indicating that biallelic pathogenic variants lead to more serious and earlier onset of symptoms. Our findings emphasize the role of PNPLA6 in different neurodegenerative disorders.

scholarly journals Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1876
Author(s):  
Julian Theuriet ◽  
Antoine Pegat ◽  
Pascal Leblanc ◽  
Sandra Vukusic ◽  
Cécile Cazeneuve ◽  
...  
Keyword(s):  
Lower Limb ◽  
Clinical Symptoms ◽  
Compound Heterozygous ◽  
Spastic Paraplegia ◽  
The Third ◽  
Limb Spasticity ◽  
Lower Limb Spasticity ◽  
Compound Heterozygous Mutations ◽  
Biallelic Mutations ◽  
Lateral Sclerosis

Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD.

scholarly journals Clear evidence of LAMA5 gene biallelic truncating variants causing infantile nephrotic syndrome

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004952021
Author(s):  
Yukimasa Taniguchi ◽  
China Nagano ◽  
Kiyotoshi Sekiguchi ◽  
Atsushi Tashiro ◽  
Noriko Sugawara ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Splice Site ◽  
Japanese Patients ◽  
Compound Heterozygous ◽  
Missense Variants ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Infantile Nephrotic Syndrome ◽  
Splice Site Variant

Background: Pathogenic variants in single genes encoding podocyte-associated proteins have been implicated in about 30% of steroid resistant nephrotic syndrome (SRNS) patients in children. However, LAMA5 gene biallelic variants have been identified in only 7 patients so far, and most are missense variants of unknown significance. Furthermore, no functional analysis had been conducted for all but one of these variants. Here, we report three patients with LAMA5 gene biallelic truncating variants manifesting infantile nephrotic syndrome and one SRNS case with biallelic LAMA5 missense variants. Methods: We conducted comprehensive gene screening of Japanese patients with severe proteinuria. Using targeted next-generation sequencing, 62 podocyte-related genes were screened in 407 unrelated patients with proteinuria. For the newly discovered LAMA5 variants, we conducted in vitro heterotrimer formation assays. Results: Biallelic truncating variants in the LAMA5 gene (NM_005560) were detected in 3 patients from 2 families. All patients presented with proteinuria within 6 months of age. Patients 1 and 2 were siblings possessing a nonsense variant (c.9232C>T, p.(Arg3078*)) and a splice site variant (c.1282+1G>A) that led to exon 9 skipping and a frameshift. Patient 3 had a remarkable irregular contour of the glomerular basement membrane. She was subsequently found to have a nonsense variant (c.8185C>T, p.(Arg2720*)) and the same splice site variant in patients 1 and 2. By in vitro heterotrimer formation assays, both truncating variants produced smaller laminin α5 proteins that nevertheless formed trimers with laminin β1 and γ1 chains. Patient 4 showed SRNS at the age of eight and carried compound heterozygous missense variants (c.1493C>T, p.(Ala498Val) and c.8399G>A, p.(Arg2800His)). Conclusions: Our patients showed clear evidence of biallelic LAMA5 truncating variants causing infantile nephrotic syndrome. We also discerned the clinical and pathological characteristics observed in LAMA5-related nephropathy. LAMA5 variant screening should be performed in congenital/infantile nephrotic syndrome patients.

scholarly journals Clinical Characteristics of POC1B-Associated Retinopathy and Assignment of Pathogenicity to Novel Deep Intronic and Non-Canonical Splice Site Variants

2021 ◽  
Vol 22 (10) ◽  
pp. 5396
Author(s):  
Nicole Weisschuh ◽  
Pascale Mazzola ◽  
Miriam Bertrand ◽  
Tobias B. Haack ◽  
Bernd Wissinger ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Splice Site ◽  
Age Of Onset ◽  
Splice Variants ◽  
Exon Skipping ◽  
Cone Dystrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Splice Site Variant

Mutations in POC1B are a rare cause of inherited retinal degeneration. In this study, we present a thorough phenotypic and genotypic characterization of three individuals harboring putatively pathogenic variants in the POC1B gene. All patients displayed a similar, slowly progressive retinopathy (cone dystrophy or cone-rod dystrophy) with normal funduscopy but disrupted outer retinal layers on optical coherence tomography and variable age of onset. Other symptoms were decreased visual acuity and photophobia. Whole genome sequencing revealed a novel homozygous frameshift variant in one patient. Another patient was shown to harbor a novel deep intronic variant in compound heterozygous state with a previously reported canonical splice site variant. The third patient showed a novel nonsense variant and a novel non-canonical splice site variant. We aimed to validate the effect of the deep intronic variant and the non-canonical splice site variant by means of in vitro splice assays. In addition, direct RNA analysis was performed in one patient. Splicing analysis revealed that the non-canonical splice site variant c.561-3T>C leads to exon skipping while the novel deep intronic variant c.1033-327T>A causes pseudoexon activation. Our data expand the genetic landscape of POC1B mutations and confirm the benefit of genome sequencing in combination with downstream functional validation using minigene assays for the analysis of putative splice variants. In addition, we provide clinical multimodal phenotyping of the affected individuals.

scholarly journals Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aliaa H. Abdelhakim ◽  
Avinash V. Dharmadhikari ◽  
Sara D. Ragi ◽  
Jose Ronaldo Lima de Carvalho ◽  
Christine L. Xu ◽  
...  
Keyword(s):  
Coenzyme Q ◽  
Clinical Manifestations ◽  
Missense Variant ◽  
Neurological Involvement ◽  
Cone Dystrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
End Stage

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

Hereditary spastic paraplegia associated with a novel homozygous intronic noncanonical splice site variant in the AP4B1 gene

2021 ◽  
Author(s):  
Clara Gómez‐González ◽  
Cristina Pizarro‐Sánchez ◽  
Carlos Rodríguez‐Antolín ◽  
Ignacio Pascual‐Pascual ◽  
Mar Garcia‐Romero ◽  
...  
Keyword(s):  
Splice Site ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Splice Site Variant

scholarly journals A case of de novo splice site variant inSLC35A2showing developmental delays, spastic paraplegia, and delayed myelination

2019 ◽  
Vol 7 (8) ◽  
Author(s):  
Sachiko Miyamoto ◽  
Mitsuko Nakashima ◽  
Tsukasa Ohashi ◽  
Takuya Hiraide ◽  
Kenji Kurosawa ◽  
...  
Keyword(s):  
Splice Site ◽  
Developmental Delays ◽  
De Novo ◽  
Spastic Paraplegia ◽  
Splice Site Variant ◽  
Delayed Myelination

scholarly journals Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1329
Author(s):  
Julia Doll ◽  
Barbara Vona ◽  
Linda Schnapp ◽  
Franz Rüschendorf ◽  
Imran Khan ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Splice Site ◽  
Genetic Heterogeneity ◽  
Bioinformatics Analysis ◽  
Molecular Genetic ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Syndromic Hearing Loss ◽  
Pakistani Families

The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.

scholarly journals Persistent Hypoglycemia with Polycystic Kidneys: A Rare Combination – A Case Report

2020 ◽  
Vol 5 (3) ◽  
pp. 1-6
Author(s):  
Priya Prasher ◽  
Katherine Redmond ◽  
Hillarey Stone ◽  
James Bailes ◽  
Edward Nehus ◽  
...  
Keyword(s):  
Case Report ◽  
Promoter Region ◽  
Molecular Genetic ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Molecular Genetic Testing ◽  
Coding Region ◽  
Polycystic Kidney ◽  
Homozygous State ◽  
Pathogenic Variants

We present the case of an infant referred to our NICU born at 39 weeks’ gestation with persistent hypoglycemia with elevated insulin levels (HI) requiring diazoxide to maintain normoglycemia. Additionally, polycystic kidney disease (PKD) was detected by ultrasound. Molecular genetic testing revealed pathogenic variants in the <i>PMM2</i>gene, i.e., a variant in the promoter region and a missense variant in the coding region. The precoding variant was recently described in 11 European families with similar phenotypes, either in a homozygous state or as compound heterozygous with a pathogenic coding variant. In neonates with HI associated with PKD, this rare recessive disorder should be considered.

Novel splice-site variant of UCHL1 in an Indian family with autosomal recessive spastic paraplegia-79

2018 ◽  
Vol 63 (8) ◽  
pp. 927-933 ◽  
Author(s):  
Aneek Das Bhowmik ◽  
Siddaramappa J. Patil ◽  
Dipti Vijayrao Deshpande ◽  
Venkatraman Bhat ◽  
Ashwin Dalal
Keyword(s):  
Splice Site ◽  
Autosomal Recessive ◽  
Spastic Paraplegia ◽  
Indian Family ◽  
Splice Site Variant

Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex

2019 ◽  
Vol 57 (4) ◽  
pp. 245-253 ◽  
Author(s):  
Kohji Kato ◽  
Yasuyoshi Oka ◽  
Hideki Muramatsu ◽  
Filipp F Vasilev ◽  
Takanobu Otomo ◽  
...  
Keyword(s):  
Core Protein ◽  
Early Stage ◽  
Critical Role ◽  
Missense Variant ◽  
Compound Heterozygous ◽  
Chondrodysplasia Punctata ◽  
Loss Of Function ◽  
Skeletal Malformation ◽  
Endosomal Membrane ◽  
Pathogenic Variants

Background3C/Ritscher-Schinzel syndrome is characterised by congenital cranio-cerebello-cardiac dysplasia, where CCDC22 and WASHC5 are accepted as the causative genes. In combination with the retromer or retriever complex, these genes play a role in endosomal membrane protein recycling. We aimed to identify the gene abnormality responsible for the pathogenicity in siblings with a 3C/Ritscher-Schinzel-like syndrome, displaying cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation.MethodsExome sequencing was performed to identify pathogenic variants. Cellular biological analyses and generation of knockout mice were carried out to elucidate the gene function and pathophysiological significance of the identified variants.ResultsWe identified compound heterozygous pathogenic variants (c.1097dup; p.Cys366Trpfs*28 and c.2755G>A; p.Ala919Thr) in the VPS35L gene, which encodes a core protein of the retriever complex. The identified missense variant lacked the ability to form the retriever complex, and the frameshift variant induced non-sense-mediated mRNA decay, thereby confirming biallelic loss of function of VPS35L. In addition, VPS35L knockout cells showed decreased autophagic function in nutrient-rich and starvation conditions, as well as following treatment with Torin 1. We also generated Vps35l−/− mice and demonstrated that they were embryonic lethal at an early stage, between E7.5 and E10.5.ConclusionsOur results suggest that biallelic loss-of-function variants in VPS35L underlies 3C/Ritscher-Schinzel-like syndrome. Furthermore, VPS35L is necessary for autophagic function and essential for early embryonic development. The data presented here provide a new insight into the critical role of the retriever complex in fetal development.

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